1. Field of the Invention
The present invention relates to pharmaceutical compositions comprising amlodipine maleate and to processes for making the same.
2. Description of the Related Arts
Calcium channel blockers are useful in treating a variety of cardiac conditions, primarily angina and hypertension. EP 089 167 and corresponding U.S. Pat. No. 4,572,909 disclose a class of substituted dihydropyridine derivatives as being useful calcium channel blockers. These patents identify that one of the most preferred compounds is 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine. This compound, which is now commonly known as amlodipine, has the following formula: 
Examples 8, 11, 12, and 22 of EP 089 167 show the synthesis of amlodipine in the maleate salt form. While a variety of acid addition salts are taught to be suitable, the maleate salt is identified as the most preferred acid addition salt.
Subsequently, EP 244 944 and corresponding U.S. Pat. No. 4,879,303 were issued directed to the besylate (or benzene sulfonate) salt of amlodipine. The besylate salt is stated to provide certain advantages over the known salts including good formulating properties. Indeed, amlodipine besylate, and not amlodipine maleate, has been developed into a commercial prescription pharmaceutical by Pfizer and is sold in the U.S. under the trade name NORVASC.
A review of the available portions of the NORVASC (amlodipine besylate) New Drug Application (NDA) filed with the U.S. Food & Drug Administration by Pfizer reveals that a switch was made during development from the original amlodipine maleate to the amlodipine besylate. (See “Review of Original NDA” for NDA# 19-787 of Oct. 10, 1990, obtainable from FDA under Freedom of Information Act). The reasons for the switch were apparently tabletting and stability problems. However, the precise stability and tabletting problems/issues/causes are not publicly disclosed in the information available from the FDA. Interestingly, clinical studies in the NDA include the use of the maleate salt form and the besylate salt form, the two salt forms being therapeutically equivalent (bioequivalent). However, in these studies amlodipine maleate was always used in a capsule or solution dosage form, not a tablet dosage form.